P4-250: Assessment of heparan-mimetics as novel Alzheimer therapeutics

Abstract

Cleavage of amyloid _–protein precursor (APP) by the protease beta–secretase (BACE1) is a key step in AÎ2 peptide processing. We have recently discovered that the cellular polysaccharide heparan sulfate (HS) is a regulator of BACE1 activity, indicating that it may play a key role in AÎ2 generation and AD pathogenesis. We have also generated heparan–mimetics with potent BACE1 inhibitory activity and low anticoagulant activity as lead compounds for a new class of AD therapeutics. They are effective at lowering AÎ2 production and do not show cytotoxicity in organotypic brain cultures. To test novel heparan–mimetics for toxicity, bioavailability and efficacy in the Tg2576 transgenic mouse model of AD. Mice were injected either with various compounds or saline and evaluated by measuring levels of AÎ2 in the brains as well as by behavioral testing. The compounds showed no evidence of toxicity at any dose. Distribution of radiolabelled compound was measured according to tissue. Pilot efficacy studies showed evidence of promise. The data provides new insights into the in vivo efficacy of heparan–mimetics as BACE1 inhibitors. These studies could underpin the development of new therapeutic strategies for human AD and other neurodegenerative disorders.